A novel
muscarinic receptor agonist
SNI-2011 ((+/-)-cis-2-methylspirol[1,3-oxathiolane-5,3'-
quinuclidine] monohydrochloride hemihydrate,
cevimeline, CAS 153504-70-2), is a candidate therapeutic
drug for
xerostomia in Sjögren's syndrome. The general pharmacological properties of this
drug on the somatic nervous system and on the autonomic nervous system and smooth muscle were investigated in mice, rats, guinea pigs, rabbits and cats. 1. Somatic nervous system:
SNI-2011 had no effect on the neuromuscular junction in rats and no muscle relaxant effect in mice. No surface
anesthetic effect was observed in guinea pigs, but infiltration
anesthetic effect was found after intracutaneous injection of
solution (1% or higher). 2. Autonomic nervous system and smooth muscle:
SNI-2011 tended to cause
mydriasis at 3 mg/kg i.v. or higher in rabbits and dose-dependently caused
mydriasis at 10 mg/kg p.o. or higher in rats.
Mydriasis in rats was also observed by ophthalmic instillation, caused via the peripheral
muscarinic acetylcholine receptors.
SNI-2011 elevated the base line tension of nictitating membrane in cats when it was injected intravenously at 3 mg/kg or higher. In the smooth muscle,
SNI-2011 increased the spontaneous movement of isolated rabbit ileum (1 x 10(-6) mol/l or higher), contractions of isolated guinea pig ileum (1 x 10(-6) mol/l or higher) and isolated guinea pig trachea (3 x 10(-6) mol/l or higher).
SNI-2011 relaxed the
histamine- and
noradrenaline-induced contractions of isolated guinea pig aorta and augmented
noradrenaline- and
phenylephrine-induced contractions of isolated rat vas deferens. These effects were induced by relatively higher concentrations only i.e. 1 x 10(-5) mol/l or higher. From these results,
SNI-2011 has
muscarinic side effects on the somatic nervous system and on the autonomic nervous system and smooth muscle, however, in the case of
oral administration, that is clinical administration route,
SNI-2011 caused no
muscarinic side effect at the effective doses needed for saliva secretion.